One of the major outcomes of the recent sequencing of the Mycobacterium tuberculosis genome was the identification of the multigene families designated PE_PGRS and PE. Since little is known about the expression or function of these genes, we have used the gene Rv1818c (PE_PGRS) and its amino-terminal PE region, as prototypes of the PE_PGRS and PE families, to investigate the immunological response to these proteins during experimental tuberculosis. Following an aerosol challenge of mice with virulent M. tuberculosis, a significant humoral immune response was mounted against the purified recombinant PE_PGRS, but not toward the recombinant PE protein. Immunoblot analysis demonstrated that sera from mice immunized with a PE_PGRS DNA construct recognized PE_PGRS but not PE, as well as a number of protein bands in lysates of M. tuberculosis. Conversely, the PE DNA construct did not elicit any humoral response directed toward PE_PGRS proteins. In animal protection studies, a DNA vaccine encoding the PE region only, generated a statistically significant reduction in number of viable bacilli in mouse tissues and reduced the lung pathology following aerosol challenge with M. tuberculosis, while the PE_PGRS encoding plasmid did not generate an effective immunity. These data demonstrate that a number of PE_PGRS proteins are expressed by M. tuberculosis, that a humoral immune response is generated only towards the PGRS domain following infection and that the PE region can elicit a protective immunity against tuberculosis. Ongoing studies are directed towards determining how the PGRS domain of this protein regulates protein stability and antigen presentation and if these effects are observed both in cis and in trans. A collaboration with Johns Hopkins University is testing the efficacy of the PE vaccine in the Rabbit model for TB.